Development and Preclinical Evaluation of a Near-Infrared Fluorescence Probe Based on Tailored Hepatitis B Core Particles for Imaging-Guided Surgery in Breast Cancer

Abstract

Rui-Qin Yang,1– 3 Min Chen,3,4 Qiang Zhang,5 Yi-Yang Gao,1– 3 Kang-Liang Lou,1– 3 Tong-Tong Lin,5 Wen-He Huang,1,2 Yun-Zhu Zeng,6 Yong-Qu Zhang,1– 3 Yong-Ying Dang,1– 3 Lei Ren,5,* Guo-Jun Zhang1,2,4,* 1Cancer Center & Department of Breast and Thyroid Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China; 2Key Laboratory for Endocrine-Related Cancer Precision Medicine of Xiamen, Xiang’an Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China; 3Clinical Central Research Core, Xiang’an Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China; 4Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China; 5State Key Lab of Physical Chemistry of Solid Surface, College of Materials, Xiamen University, Xiamen, Fujian, People’s Republic of China; 6The Pathology department, Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-Jun Zhang, Tel [phone], Fax [phone], Email [email protected]: Tumor-free surgical margin is crucial but challenging in breast-conserving surgery (BCS). Fluorescence imaging is a promising strategy for surgical navigation that can reliably assist the surgeon with visualization Of the tumor in real-time. Notably, finding an optimized fluorescent probe has been a challenging research topic. Herein, we developed a novel near-infrared (NIR) fluorescent probe based on tailored Hepatitis B Core virus-like protein (HBc VLP) and presented the preclinical imaging-guided surgery.Methods: The RGD-HBc160 VLP was synthesized by genetic engineering followed encapsulation of ICG via disassembly-reassembly. The applicability of the probe was tested for cell and tissue binding capacities through cell-based plate assays, xenograft mice model, and MMTV-PyVT mammary tumor transgenic mice. Subsequently, the efficacy of RGD-HBc160/ICG-guided surgery was evaluated in an infiltrative tumor-bearing mouse model. The protein-induced body’s immune response was further assessed.Results: The prepared RGD-HBc160/ICG showed outstanding integrin αvβ3 targeting ability in vitro and in vivo. After intravenous administration of probe, the fluorescence guidance facilitated more complete tumor resection and improved overall survival Of the infiltrative tumor-bearing mice. The probe also showed the excellent capability to differentiate between benign and malignant breast tissues in the mammary tumor transgenic mice. Interestingly, the ingenious tailoring of HBc VLP could not only endow its tumor-targeting ability towards integrin αvβ3 but also significantly reduce the humoral and cellular immune response.Conclusion: The RGD-HBc160/ICG holds promise as an effective tool to delineate tumor margin. These results have translational potential to achieve margin-negative resection and improve the stratification of patients for a potentially curative.Graphical Abstract: Keywords: breast Cancer, tumor margin, NIR fluorescence imaging, imaging-guided surgery, Hepatitis B core virus-like particles

Keywords

• breast cancer
• tumor margin
• nir fluorescence imaging
• imaging-guided surgery
• hepatitis b core virus-like particles